Diagnosis and management of miliary tuberculosis: current state and future perspectivesSayantan Ray, Arunansu Talukdar, Supratip Kundu, Dibbendhu Khanra, and Nikhil SonthaliaAuthor information ► Copyright and License information ►This article has been retracted. See Ther Clin Risk Manag. 2015 September 28; 11: 1457.This article has been cited by other articles in PMC.Go to:

AbstractTuberculosis (TB) remains one of the most important causes of death from an infectious disease, and it poses formidable challenges to global health at the public health, scientific, and political level. Miliary TB is a potentially fatal form of TB that results from massive lymphohematogenous dissemination of Mycobacterium tuberculosis bacilli. The epidemiology of miliary TB has been altered by the emergence of the human immunodeficiency virus (HIV) infection and widespread use of immunosuppressive drugs. Diagnosis of miliary TB is a challenge that can perplex even the most experienced clinicians. There are nonspecific clinical symptoms, and the chest radiographs do not always reveal classical miliary changes. Atypical presentations like cryptic miliary TB and acute respiratory distress syndrome often lead to delayed diagnosis. High-resolution computed tomography (HRCT) is relatively more sensitive and shows randomly distributed miliary nodules. In extrapulmonary locations, ultrasonography, CT, and magnetic resonance imaging are useful in discerning the extent of organ involvement by lesions of miliary TB. Recently, positron-emission tomographic CT has been investigated as a promising tool for evaluation of suspected TB. Fundus examination for choroid tubercles, histopathological examination of tissue biopsy specimens, and rapid culture methods for isolation of M. tuberculosis in sputum, body fluids, and other body tissues aid in confirming the diagnosis. Several novel diagnostic tests have recently become available for detecting active TB disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. A high index of clinical suspicion and early diagnosis and timely institution of antituberculosis treatment can be lifesaving. Response to first-line antituberculosis drugs is good, but drug-induced hepatotoxicity and drug–drug interactions in HIV/TB coinfected patients create significant problems during treatment. Data available from randomized controlled trials are insufficient to define the optimum regimen and duration of treatment in patients with drug-sensitive as well as drug-

resistant miliary TB, including those with HIV/AIDS, and the role of adjunctive corticosteroid treatment has not been properly studied. Research is going on worldwide in an attempt to provide a more effective vaccine than bacille Calmette–Guérin. This review highlights the epidemiology and clinical manifestation of miliary TB, challenges, recent advances, needs, and opportunities related to TB diagnostics and treatment.

Keywords: Mycobacterium tuberculosis, human immunodeficiency virus, diagnostic tests, biomarkers, antituberculosis drugs, vaccineGo to:

IntroductionTuberculosis (TB) is a leading cause of preventable morbidity and mortality worldwide. The latest World Health Organization (WHO) figures indicate that in 2010 there were 8.8 million incident cases of TB, with 13% of cases occurring among patients with human immunodeficiency virus (HIV) infection.1,2 The disease primarily involves the lungs, and at times distant blood-borne spread results in the development of extrapulmonary TB (EPTB). Miliary TB is a pathological name describing millet seed-sized (1–2 mm) granulomas in various organs affected by tubercle bacilli.3 It results from massive lymphohematogenous dissemination from a Mycobacterium tuberculosis-laden focus. In 1700, John Jacob Manget coined the term “miliary TB” (derived from the Latin word “miliarius,” meaning related to millet seed) to denote this lethal form of disseminated TB.4–6 In order to clarify the difference between clinical and pathological diagnoses, it has been proposed that the term miliary TB should be restricted to disseminated TB with miliary shadows on chest radiograph.7

Miliary TB has a spectrum of manifestations that still perplex the most erudite and experienced clinicians and are a diagnostic and therapeutic challenge. Despite effective therapy being available, mortality from this disease has remained high. The myriad clinical manifestations, atypical radiographic findings, and difficulties in establishing TB as the etiological diagnosis are challenges in the diagnosis and treatment of miliary TB.

Miliary TB is diagnosed by the presence of a diffuse miliary infiltrate on chest radiograph or high-resolution computed tomography (HRCT) scan, or evidence of miliary tubercles in multiple organs at laparoscopy, open surgery, or autopsy. The clinical and morbid anatomic picture needs to be confirmed by bacteriology, histopathology, and/or a dramatic chemotherapeutic response. The disease is characterized by high mortality, reported to be between 18% and 30%. The diagnosis is frequently missed, and more invasive investigations are often required.

In this review, we first provide an overview regarding the epidemiology, current understanding of key pathogenetic mechanisms, and the varied clinical

manifestations in miliary TB, and then the available diagnostic modalities with recent advances and current treatment guidelines of miliary TB are addressed in detail.

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Burden of the problemTB remains a major worldwide health problem, causing almost 2 million deaths every year. The epidemic of TB, fuelled by HIV coinfection and bacillary resistance to current antimycobacterial drugs, continues to plague low-income countries particularly. India bears the highest burden of TB (1.96 million cases annually),8 and also a significantly high number of HIV patients (2.3 million prevalent cases).9

It is estimated that miliary TB accounts for about less than 2% of all cases of TB in immunocompetent persons and up to 20% of all EPTB cases. Of 11,182 incident cases reported in the United States in 2010, EPTB accounted for approximately 22% of cases; miliary disease was reported in 299 (2.7%).10 Immunocompromised patients have a significantly higher prevalence of TB than the general population. The disease is more frequently encountered in immunosuppressed individuals. EPTB accounts for more than 50% of all cases of TB in late HIV infection.11–18 This disease has shown a high mortality, despite effective therapy being available. Worldwide, estimates of its incidence are hampered largely by incomplete reporting and imprecise diagnostic criteria.

Since its first description by John Jacob Manget, the clinical presentation has changed dramatically. Miliary TB has been considered to be a childhood disease for a long time. However, during the last three decades, it is increasingly being recognized in adults also.19–21 It has been noticed recently that there is an increase in the incidence of miliary TB owing to the HIV epidemic, and the increasing list of causes of immunosuppression, such as introduction of biological and immunosuppressive drugs for treatment of various medical disorders, increasing occurrence of organ transplantation, and chronic hemodialysis programs. Bacille Calmette–Guérin (BCG) vaccination has resulted in substantial reduction in miliary TB and TB meningitis (TBM) among young vaccines. Increasing use of CT scans and wider application of invasive diagnostic methods are likely to have contributed to the demographic shift. At present, two additional peaks are evident: one involving adolescents and young adults, and the other later in life among elderly persons.5,22,23–36 Males appear to be more frequently affected by miliary TB in pediatric as well as adult series.21–38

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Pathogenesis

The central event in the development of miliary TB is a massive lymphohematogenous dissemination of M. tuberculosis from a pulmonary or extrapulmonary focus and embolization to the vascular beds of various organs. It most commonly involves the liver, spleen, bone marrow, lungs, and meninges. The most likely reason for this distribution is that these organs have numerous phagocytic cells in their sinusoidal wall. Sometimes, simultaneous reactivation of multiple foci in various organs can result in miliary TB. This reactivation can occur either at the time of primary infection or later during reactivation of a dormant focus. When miliary TB develops during primary disease (early generalization), the disease has an acute onset and is rapidly progressive. Late generalization during postprimary TB can be rapidly progressive (resulting in acute miliary TB), episodic, or protracted, leading to chronic miliary TB. Reinfection also has an important role, particularly in highly endemic areas with increased transmission of M. tuberculosis.

The inadequacy of effector T-cell response in suppression of M. tuberculosis is thought to be responsible for the development of miliary TB.39–42 The abundance of T-helper 1 and 2 polarized effector T (Teff) cells in the peripheral blood as well as at local disease site(s) of patients with miliary TB suggests that miliary TB possibly represents the T-helper 2 end of the spectrum.41,42 Interleukin-4 (IL-4), with its ability to downregulate inducible nitric oxide synthase, toll-like receptor 2, and macrophage activation, may play a crucial role in determining whether the infection becomes latent or progressive.39,40M. tuberculosis can either fail to induce the protective response or can drive the protective mechanisms and then deliberately “sabotage” them, resulting in progressive disease.40–42 In miliary TB, the selective recruitment of the Teff cells at the pathologic site, however, fails to provide an adequate level of effector immunity at the disease site due to efficient and comparable homing of regulatory T (Treg) cells, which inhibit the function of the Teff cells that have infiltrated the disease site. It has been postulated that when the balance of homing shifts toward the Treg cells, there occurs a state of local immunosuppression leading to disease dissemination.

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Clinical presentationThe clinical manifestations of miliary TB are protean, nonspecific, and can be obscure till late in the disease.

Constitutional symptoms

Presentation with fever of several weeks’ duration, anorexia, weight loss, lassitude, and cough is frequent. Occurrence of daily morning temperature spikes is reported to be characteristic of miliary TB.43 However, fever may be absent

and the patients may present with progressive wasting strongly mimicking a metastatic carcinoma (cryptic miliary TB).21,44,45 Previously, cryptic miliary TB, which was often diagnosed only at autopsy, is now being increasingly diagnosed with the advent of HRCT. Chills and rigors, described in patients with malaria, or sepsis and bacteremia, have often been described in adult patients with miliary TB.46 Night sweats are common.

Systemic involvement

Since miliary TB can involve many organs, patients present with symptoms and signs referring to various organ systems. TBM has been described in 10%–30% of adult patients with miliary TB.23–38 On the contrary, about one-third of patients presenting with TBM have underlying miliary TB.47 A recently published study48 found TBM with and without tuberculomas and thoracic transverse myelopathy as the most frequent neurological complication in patients with miliary TB.

Choroidal tubercles occur less commonly in adult patients with miliary TB than children. If present, choroidal tubercles are pathognomonic of miliary TB and offer a valuable clue to the diagnosis (Figure 1A and B). Choroidal tubercles are bilateral, pale, gray-white, or yellowish lesions usually less than one-quarter of the size of the optic disk and are located within 2 cm of the optic nerve. Therefore, a systematic ophthalmoscopic examination after mydriatic administration is recommended in all patients with suspected miliary TB.

Figure 1(A) Ophthalmoscopic pictures showing multiple choroidal tubercles (black arrows); (B) choroidal tubercles (white arrows): fluorescein angiogram.

Cutaneous lesions may offer a valuable clue to the diagnosis of miliary TB. Skin involvement in the form of erythymatosus macules and papules has also been described.3–6 Signs of hepatic involvement may be evident in the form of icterus and hepatosplenomegaly. Before the advent of modern imaging modalities, such as CT, MRI, and echocardiography, clinically evident cardiac or renal involvement was seldom documented in patients with miliary TB.3–6 Overt adrenal insufficiency at presentation or during treatment has also been described in miliary TB.49 Atypical presentations21,25–38,44,48–66 can delay the diagnosis, and miliary TB is often a missed diagnosis. Patients with occult miliary TB can present with “pyrexia of unknown origin” without any localizing clue. Clinical presentation such as absence of fever and progressive wasting strongly mimicking a metastatic carcinoma can occur, especially in the elderly. Proudfoot

et al21 suggested the term “cryptic miliary TB.” Few studies have highlighted the important differences between classical and cryptic forms of miliary TB.21,44,45

Children

By contrast with adults, fewer published series are available on childhood miliary TB.67–71 Clinical presentation of miliary TB in children is similar to that observed in adults. In children with miliary TB, chills, night sweats, hemoptysis, and productive cough have been reported less frequently, while peripheral lymphadenopathy and hepatosplenomegaly are more common, compared with adults. A higher proportion of children with miliary TB (20%–40%) suffer from TBM67–71 compared with adults.

Immunosuppressed individuals

The clinical presentation of miliary TB in early HIV infection (CD4+ cell counts > 200 cells/μL) is similar to that observed in immunocompetent individuals.72–74 With progression of immunosuppression in late, advanced HIV infection (CD4+ cell counts < 200 cells/μL), disseminated and miliary TB are seen more often.15,75 A number of studies have addressed the comparison of various aspects of miliary TB in the late advanced stage of HIV infection and in immunocompetent individuals.15,72,75–77 Cutaneous involvement is unusual in miliary TB, but is more commonly seen in HIV-infected patients with severe immunosuppression.78 Typically, the cutaneous lesions are few in number and appear as tiny papules or vesiculopapules,79 described as tuberculosis cutis miliaris disseminata, tuberculosis cutis acuta generalisita, and disseminated TB of the skin. Sometimes, macular, pustular, or purpuric lesions, indurated ulcerating plaques, and subcutaneous abscesses have been reported.79

In miliary TB patients coinfected with HIV, intrathoracic lymphadenopathy and tuberculin anergy are more common; sputum smears are seldom positive, and blood culture may grow M. tuberculosis, especially with profound immunosuppression.72–74

Immune reconstitution inflammatory syndrome (IRIS) has been implicated as the cause of paradoxical worsening of lesions in patients with TB. IRIS has been reported to occur in about one-third of patients with HIV/TB coinfection within days to weeks of the initiation of highly active antiretroviral therapy. IRIS can be brief or prolonged with multiple recurrences. Manifestations of IRIS range from isolated instances of fever to increased or initial appearance of lymphadenopathy, new or worsening pulmonary infiltrates, serositis, cutaneous lesions, and new or expanding central nervous system (CNS) mass lesions.80 Consequently, HIV/miliary TB coinfected patients may develop acute renal failure81 or acute respiratory distress syndrome (ARDS).82

Uncommon clinical manifestations and complications

Several uncommon clinical manifestations and complications have been observed in patients with miliary TB (Table 1).21,25–38,44,50–66 Atypical clinical presentation often delays diagnosis and treatment, and miliary TB is often a “missed diagnosis.”

Table 1Uncommon clinical manifestations and complications in miliary tuberculosis

Complications are often self-limited and improve with antituberculosis therapy (ATT) alone. However, at times they can be life-threatening, necessitating prompt recognition and treatment. Important complications in patients with miliary TB include air-leak syndromes (eg, pneumothorax, pneumopericardium), ARDS, antituberculosis drug-induced hepatotoxicity, and renal failure. Rarely, cardiovascular complications and sudden cardiac death have been described in miliary TB.61–65

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DiagnosisEven in the endemic area, the diagnosis of miliary TB can be difficult, as the clinical symptoms are nonspecific, the chest radiographs do not always reveal the classical miliary changes, and atypical presentations are commonly encountered. Therefore, a high index of clinical suspicion and a systematic approach to diagnostic testing is required to establish the diagnosis of miliary TB.

The following criteria have been proposed for the diagnosis of miliary TB:35 (1) clinical presentation consistent with the diagnosis of TB – like pyrexia with evening rise of temperature, night sweats, anorexia, and weight loss of greater than 6 weeks in duration – responding to antituberculosis treatment; (2) typical miliary pattern on chest radiograph; (3) bilateral, diffuse reticulonodular lung lesions on a background of miliary shadows demonstrable either on chest radiograph or HRCT scan; and (4) microbiological or histopathological evidence of TB.

A high index of clinical suspicion with efforts towards confirming the diagnosis by demonstrating M. tuberculosis early in the course of disease is imperative. Smear and culture examination of spontaneously expectorated or induced sputum,

gastric lavage, pleural, peritoneal, or pericardial fluid, cerebrospinal fluid, urine, pus from cold abscess, bronchoscopic secretions, and peripheral blood is helpful in the diagnosis of miliary TB. Microbiological and histopathological examination of bone marrow, liver and peripheral lymph node, and transbronchial lung biopsy specimens have all been used to confirm the diagnosis of miliary TB, with varying results.25,32–36,83 Whenever possible, efforts should be made at procuring tissue/fluid for mycobacterial culture and sensitivity testing. Rapid-culture methods such as the Bactec 460 radiometric method or Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system may be useful for rapid drug-susceptibility testing.17,84 In the published reports, no systematic pattern of diagnostic approach is available. A standard diagnostic approach to a patient with suspected miliary TB is shown in Figure 2.

Figure 2Algorithm for the diagnostic workup of a patient with suspected miliary tuberculosis (TB).

Laboratory findings

Hematological and biochemical

A number of hematological and biochemical abnormalities are known to occur in patients with miliary TB.23–30,33–38,67–69 Anemia of chronic disease, leukocytosis, leucopenia, leukamoid reactions, and thrombocytopenia are some of the common abnormalities found. Erythrocyte sedimentation rate is usually elevated in patients with miliary TB. Disseminated intravascular coagulation has been described in patients with miliary TB in the setting of ARDS and multiple organ dysfunction syndrome and is associated with a high mortality.85 Immune mechanisms have been implicated to cause bone marrow suppression and resulting pancytopenia or hypoplastic anaemia.56

Hyponatremia in miliary TB can occur due to an acquired disturbance of neurohypophyseal function resulting in unregulated antidiuretic hormone release. Hyponatremia may indicate the presence of TBM36 and may also be a predictor of mortality.26,35 Hypercalcemia has also been described in miliary TB, but is uncommon.

Tuberculin skin test

A higher proportion of patients with miliary TB manifest tuberculin anergy than those with pulmonary TB or EPTB. Tuberculin skin test (TST) conversion may occur following successful treatment. In various published pediatric67–71 and adult series,4,24–29,32–34,37 tuberculin anergy has ranged from 35% to 74% and 20% to 70%, respectively. Because of tuberculin anergy, cross-reactivity with environmental mycobacteria and tuberculin positivity due to BCG vaccination, the TST is not useful as a diagnostic test in patients with miliary TB. Tuberculin test positivity suggests infection, but it does not distinguish between latent TB infection and active disease. Although a positive TST signifies a possible diagnosis of miliary TB, a negative test does not exclude it.

Interferon-gamma release assays

Currently, two commercial interferon-γ release assays (IGRAs), the Quantiferon-TB Gold (QFT-G) and the T-Spot-TB, are approved. They measure interferon-γ released following incubation of patient blood with antigens specific to M. tuberculosis, namely early secretory antigenic target-6 (ESAT-6) and culture filtrate protein 10 (CFP-10). The QFT-G test is now available as an “in-tube” version, which also includes, in addition to ESAT-6 and CFP-10, the antigen TB7.7.86 IGRAs do not differentiate latent TB infection from active TB disease and are not significantly superior to TST, albeit they have the ability to identify latent TB infection in HIV-infected individuals.86,87 The WHO advises against the use of IGRAs over TST as a diagnostic test in low- and middle-income countries with typically high TB and/or HIV burdens.88

Imaging studies

Miliary pattern on the chest radiograph is often the first clue suggestive of miliary TB. Several other imaging modalities, such as ultrasonography, CT, MRI, and positron-emission tomography (PET), help to assess the extent of organ involvement and are also useful in evaluating response to treatment.

Chest radiograph

The radiographic hallmark of miliary TB is the miliary pattern on chest radiograph (Figure 3A). The term miliary refers to the “millet seed” size of the nodules (<2 mm) seen on classical chest radiograph. Subtle miliary lesions are best delineated in slightly underpenetrated films, especially when the areas of the lung in between the ribs are carefully scrutinized.89,90 The chest radiographic abnormalities in miliary TB are described in Table 2.4 In about 10% of cases, the nodules may be greater than 3 mm in diameter.78 Chest plain films are usually normal at the onset of symptoms, and the earliest finding, seen within 1–2 weeks, may be hyperinflation. As the typical changes evolve over the course of disease, obtaining periodic chest radiographs in patients presenting with pyrexia of unknown origin may be rewarding. In the pre-CT scan era, diagnosis of miliary TB was frequently missed on the chest radiographs and was evident only at

autopsy. Evidence from published studies indicates that the classic miliary pattern may not be evident in up to 50% of patients with miliary TB.23–26,90

Figure 3(A) Chest radiograph (posteroanterior view) showing classical miliary pattern. (B) High-resolution computed tomography image (1.0 mm section thickness) shows uniform-sized small nodules randomly distributed throughout both lungs. Note the classical “tree-in-bud” ...

Table 2Chest radiographic abnormalities in miliary tuberculosis

A classical miliary pattern on the chest radiograph represents the summation of densities of tubercles that are perfectly aligned, whereas curvilinear densities and reticulonodular pattern result from imperfectly aligned tubercles.91 The histopathological composition of the tubercles, their number, and their size have been proposed to be the determinants of radiographic visibility of the nodules.92,93 Rarely, lymphatic obstruction or infiltration can result in ground-glass appearance.92 The diagnosis of miliary TB becomes easier when a patient presents with typical miliary shadows on chest radiograph in an appropriate setting, as compared to those who do not show the classical pattern. Thus, if there is a high index of suspicion of miliary TB and the chest radiograph is atypical, it is suggested that HRCT be done to support the diagnosis.

Ultrasonography

In patients with miliary TB, ultrasonography is a useful tool in detecting associated lesions, such as loculated ascites, focal hepatic and splenic lesions, adnexal mass, intra-abdominal lymphadenopathy, and cold abscess. Ultrasonography guidance also facilitates diagnostic thoracic or abdominal paracentesis to procure pleural or peritoneal fluid for diagnostic testing, especially if the fluid is loculated.

Computed tomography and magnetic resonance imaging

In comparison with the pre-CT era, HRCT scans have considerably improved the antemortem diagnosis of miliary TB and may demonstrate miliary disease before it becomes radiographically apparent. On a thin-section CT, a mixture of both sharply and poorly defined 1–4 mm nodules are seen in a diffuse, random distribution often associated with intra- and interlobular septal thickening (Figure 3B).93 The interlobular septal thickening or intralobular fine network that is evident on HRCT scans in miliary TB seems to be caused by the presence of tubercles in the interlobular septa and alveolar walls. Sometimes, in subjects with active postprimary disease, centrilobular nodules and branching linear structures with a “tree-in-bud” appearance may be evident.94 Contrast-enhanced CT scans are better for detecting additional findings, such as intrathoracic lymphadenopathy, calcification, and pleural lesions. A higher prevalence of interlobular septal thickening, necrotic lymph nodes, and extrathoracic involvement has been observed in HIV-seropositive patients with miliary TB.76

Miliary TB is an interstitial lung disease (ILD), having clinical, radiological, and physiological similarities with other ILDs. As a result of the similarity of miliary TB with other ILDs, it poses diagnostic and therapeutic challenges to physicians. It has to be emphasized that an early and definite diagnosis of miliary TB is of paramount importance as it is a treatable condition, whereas most other ILDs do not have a specific treatment. On this issue, Pipavath and colleagues95 describe the HRCT findings and correlation of these findings with pulmonary function and gas-exchange parameters in miliary TB. In addition to the demonstration of miliary nodularity in HRCT, this study has demonstrated other radiological features (consolidation, ground-glass, and focal cystic abnormalities), which cannot be seen in chest radiographs. Another important HRCT finding from this study is the demonstration of emphysematous changes following treatment. They have also demonstrated that HRCT findings correlate with restrictive physiology and impaired gas exchange, as in other interstitial lung diseases.95

Contrast-enhanced CT and MRI have been useful in identifying miliary lesions at occult extrapulmonary sites, an exercise that was earlier possible only at postmortem examination. Abdominal CT is useful in identifying lesions in the liver, spleen, mesentery, peritoneum, and intra-abdominal lymphadenopathy, and also detects cold abscesses.17,96 Unlike HRCT scans of the chest, where the classic nodular lesions are less than 2 mm, miliary lesions in the liver and spleen may appear as confluent or discrete hypodense lesions (Figure 3C and D), sometimes with peripheral rim enhancement.17,96

Miliary CNS TB is usually associated with TBM and appears at MRI as multiple tiny, hyperintense T2 foci that homogeneously enhance on contrast enhanced T1-weighted images (Figure 3E). The MRI is particularly helpful in identifying and delineating the extent of tuberculomas and cold abscesses and monitoring the response to treatment.

Pelvic evaluation with all imaging modalities should be routinely done in all female patients for defining the extent of involvement. Image-guided radiological procedures such as fine-needle aspiration for cytological examination and biopsy under CT or MRI guidance are useful for procuring tissue/body fluids for diagnostic testing.

Positron-emission tomography

PET-CT using the radiopharmaceutical 18F fluorodeoxyglucose has the potential to play a role in assessing the activity of various infectious lesions, including TB.97,98 The PET-CT is suitable for defining the extent of disease at the time of initial presentation (Figure 4A and B). Though 18F fluorodeoxyglucose PET/CT is not specific for TB, it plays an important role in the evaluation of known or suspected TB cases. It can determine the activity of lesions, guide biopsy from active sites, detect occult distant foci, and evaluate response to therapy. In the future, labeling antituberculous drugs like isoniazid and rifampicin with positron-emitting isotopes may culminate in the development of TB-specific PET radiopharmaceuticals.

Figure 4Coronal plain computed tomography (A) and positron-emission tomography (B) images showing diffuse increased 18F fluorodeoxyglucose uptake in spleen and multifocal uptake in liver, mediastinal node (black arrow).

Pulmonary functions, gas-exchange abnormalities

Miliary TB is associated with abnormalities of pulmonary function typical of diffuse interstitial disease of the lungs.99,100 Impairment of diffusion has been the most frequent and severe abnormality encountered.100 Additionally, a mild reduction in flow rates suggestive of peripheral airways involvement may be observed.101 During the acute stage, arterial hypoxemia due to widening of the alveolar–arterial oxygen gradient and hypocapnia due to tachypnea are also observed. These patients have abnormal cardiopulmonary exercise performance, with lower maximum oxygen consumption, maximal work rate, anaerobic threshold, peak minute ventilation, breathing reserve, and low maximal heart rate.102,103 Some of these patients manifest a demonstrable fall in oxygen saturation (to 4% or more) with exercise. Following successful treatment, most patients reveal reversal of abnormalities. However, some of these abnormalities may persist following treatment.102,103

Sputum examination – staining and culturing

Though not all patients with miliary TB manifest productive cough, when available, sputum must be subjected to smear and mycobacterial culture examination. Sputum smear microscopy using Ziehl–Neelsen staining is useful in detecting acid-fast bacilli. Fluorescence microscopy is credited with increased sensitivity and lower work effort, but has a rider of increased cost and technical complexity. Various developments are being made in the field of fluorescent microscopy, including light-emitting diode-based fluorescent microscopy, mobile phone-based microscopy, and automated detection systems using image processing.104

Culture remains the gold standard for the laboratory confirmation of TB. Although culture-based diagnosis of TB is recommended in the International Standards of Tuberculosis Care,105 lack of resources and technical expertise poses a major limitation in most of the high-prevalence countries. Traditionally, primary isolation and culture of mycobacteria is performed on Löwenstein–Jensen medium, which takes at least 21 days for a result. Liquid culturing with radioisotopic detection or with the incorporation of fluorescent dyes was introduced in the past as a confirmatory method (Bactec 460, Bactec MGIT 960 system, MB/BacT, and Versa Trek system). The mean turnaround time for mycobacterial growth in smear-positive specimens is 9 days for MGIT 960 and 38 days for Löwenstein–Jensen medium, whereas in smear-negative specimens it is 16 and 48 days, respectively.106 Microscopic observation drug susceptibility testing developed recently allows both rapid and low-cost TB diagnosis in liquid culture with the simultaneous determination of drug susceptibilities.107 Some other unconventional methods, like thin-layer agar and the direct nitrate reductase assay, have attempted to address the problem of multiple-point processing and hence the generation of aerosols by incorporating visual inspection of results in the form of typical colony morphology or color change to identify TB growth.108

Bronchoscopy

Fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), bronchoscopic aspirate, brushings, washings, and transbronchial lung biopsy are useful in confirming the diagnosis of miliary TB. The cumulative diagnostic yield for various bronchoscopic specimens by smear and culture methods in published studies has been found to be 46.8%.32–36 In patients with dry cough, BAL fluid obtained through fiberoptic bronchoscopy should be submitted for mycobacterial smear, culture, and molecular methods.

Body-fluid and tissue examination

In patients with suspected miliary TB, depending on the extent of organ-system involvement, appropriate tissue and body-fluid samples must be obtained to confirm histopathological microbiological diagnosis. Elevated serum alkaline phosphatase levels indicate diffuse liver involvement; needle biopsy of the liver can be useful in confirming the diagnosis. Bone marrow aspiration and needle

biopsy have also been found to be useful for the diagnosis of miliary TB. Pleural fluid, pericardial fluid, ascitic fluid, cerebrospinal fluid (CSF), urine, bronchoscopic secretions, blood and tissue biopsy specimens have all been employed to confirm the diagnosis of disseminated and miliary TB. The diagnostic yield of various tissue and body-fluid specimens has been variable.23–30,32–37,67–69

Immunological abnormalities

A limited number of reports on the cellular characteristics of BAL in patients with miliary TB have been published, with conflicting results.100,101,109 Patients with TB had a significantly higher total cell count and increased proportion of lymphocytes and CD3+ and CD4+ T lymphocytes in the BAL fluid.101 In patients with miliary TB, BAL showed lymphocytic alveolitis.101,109 The finding of increased CD4+ lymphocytes in the BAL fluid and their depletion in the peripheral blood suggested compartmentalization of lymphocytes at the site of inflammation.

Polyclonal hypergammaglobulinemia with increase in immunoglobulin (Ig) G, IgA, and IgM was observed in peripheral blood and BAL fluid in one study.101 These findings probably result from increased local synthesis by activated B lymphocytes. Increased BAL fluid fibronectin101,110 and serum complement (C3)101 have also been described in patients with miliary TB. The increase in serum C3 has been thought to be the result of “acute-phase response” to ongoing inflammation and elevated BAL fluid fibronectin compared with peripheral blood suggest local synthesis in the lung.

Serodiagnostic and molecular methods

When ascitic or pleural fluid is present, adenosine deaminase (ADA) and interferon-γ estimations can be useful adjuncts in the diagnosis, especially in areas where TB is highly prevalent.17,111–113 A recent study114 has shown that that CSF-ADA is a more sensitive indicator than polymerase chain reaction (PCR) for the diagnosis in patients with TB meningitis. As ADA estimation is a cheap, cost-effective test, the utility of CSF-ADA estimation in the diagnosis of TB meningitis merits further study. PCR of blood (especially in HIV-infected patients), CSF fluid, and tissue biopsy specimens may be useful for confirmation of diagnosis.17 PCR has been found to be most useful when applied to clean specimens such as CSF fluid, where its sensitivity and specificity have been reported to be 50%–90% and 100%, respectively.17 In patients with suspected miliary TB, wherever possible, automated molecular tests for M. tuberculosis detection and drug-resistance testing may be used for early confirmation of diagnosis.115 The PCR-based amplification of various target nucleic acids has been tried extensively that allows rapid and sensitive detection of target DNA sequences. The PCR amplification of the entire 16S–23S rRNA spacer region and use of a secondary technique of randomly amplified polymorphic DNA fingerprinting to differentiate strains belonging to the Mycobacterium genus has

been reported.116 Other targets include the 16S rRNA gene, the 16S–23S internal transcribed spacer, the 65 kDa heat-shock protein, recA, rpoB, and gyrB.

The most significant advance toward a point-of-care (POC) test for TB has come in the field of nucleic acid amplification with the launch of the GeneXpert MTB/RIF assay.117 The assay is capable of detecting the M. tuberculosis complex while simultaneously detecting rifampicin resistance within 2 hours. When testing a single sputum sample, the assay detects 98%–100% of sputum smear-positive disease and 57%–83% of smear-negative disease among prospectively studied TB suspects.118 Based on currently available evidence and expert opinion, molecular assays to detect gene mutations that signal drug resistance have been endorsed by the WHO as being most suited for rapid diagnosis.115 Urine represents a clinical sample that is easy to collect from both adults and children, and has been used extensively to evaluate several antigen and DNA detection assays.119 Commercially available assays are able to detect lipoarabinomannan (LAM) in the urine of patients with TB. A cheap POC lateral flow (Determine TB-LAM Ag urine dipstick test) has now been developed, which provides a qualitative (yes/no) readout of a TB diagnosis.120

The ideal TB test would be a POC device capable of providing an on-the-spot accurate diagnosis of active TB in HIV-infected and -uninfected adults and children with pulmonary and EPTB; it should also be able to detect resistance to the first-line TB drugs to avoid initial treatment failure.121 Table 3 summarizes the strengths and limitations of the currently available tests for TB.

Table 3Key features of tests for TB

In geographical areas where the prevalence of TB is high, when a patient presents with a compatible clinical picture and a chest radiograph suggestive of classical miliary pattern, it is common practice to start the ATT straight away, keeping in mind the potential lethality of the condition. Measures to confirm the diagnosis are initiated simultaneously.

The Indian perspective

Scientific efforts have been put in by academia and research institutes in India for the development of better diagnostic tools. India has been a big market for in vitro

diagnostics, but has been dominated by imported and generic products, mostly serological, with virtually no innovations. The Revised National Tuberculosis Control Programme (RNTCP), being an official caretaker in India for TB control, has been very active in the recent past. In line with the WHO twelve-point policy package, RNTCP has also adopted strategies to diagnose and manage TB in HIV-infected patients. The program has immediate priorities of restricting TB infection by providing treatment to all infected individuals. For diagnosis, there exist the guidelines for intensive case-finding at the community level, but for early diagnosis of TB in the Indian population, not many efforts could be made. This is very justifiable in the light of huge numbers of already existing cases of TB. The Indian Council of Medical Research (ICMR) has also been working extensively on disease-control programs with the support of the continued exploitation of scientific and technological advances from basic to applied research, from biomedical to health sciences, and from laboratory to field research. ICMR is providing significant information through its laboratories engaged in TB research and also provides funding to various academic and research institutions for research in this area.

An international symposium on TB diagnostics held at the International Centre for Genetic Engineering and Biotechnology, New Delhi, India, in December 2010 titled “Innovating to Make an Impact” discussed multiple aspects regarding the challenges in TB diagnostics. A very positive feel for support in the field of diagnostic development came out of this.122 A consultative meeting held in January 2011 at the National AIDS Research Institute, India, – “Galvanizing Evidence for HIV Management” – also incorporated a full session on TB supported by WHO. Exclusive discussions on diagnosing EPTB, childhood TB, and HIV-TB were conducted, as these pose serious challenges to developing universally applicable diagnostic tools for TB. The willingness and determination for better diagnosis and management of TB from laboratory workers to the policy-makers have further shown a promising future.

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TreatmentMiliary TB is uniformly fatal within 1 year if untreated.3–6 ATT is the cornerstone of management. Delay in diagnosis often leads to late institution of specific treatment and significantly contributes to mortality. A greater vigilance with efforts towards confirming the diagnosis by demonstrating M. tuberculosis early in the course of disease is imperative. There is no consensus regarding the optimum duration of treatment in patients with miliary TB. Moreover, published randomized controlled trials assessing the efficacy of the standard WHO treatment regimens that have been widely used in national TB-control programs are also lacking.123,124 We will discuss the treatment of miliary TB as per the current recommendations by different authoritative bodies in the following sections.

Guidelines from professional organizations

According to the WHO guidelines,123 patients are categorized as “new patients” or “previously treated patients.” Miliary TB is classified as pulmonary TB because there are lesions in the lungs. New patients with miliary TB receive 6 months of daily or intermittent treatment. The guidelines mention that some experts recommend 9–12 months of treatment when TBM is present given the serious risk of disability and mortality, and 9 months of treatment when bone and joint TB is also present.

In the absence of associated meningeal involvement, the American Thoracic Society, the Centers for Disease Control and Prevention (CDC), the Infectious Disease Society of America,125 and the National Institute for Health and Clinical Excellence (NICE) TB guidelines126 suggest 6 months of treatment (2-month intensive phase with isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin, followed by a 4-month continuation phase with isoniazid and rifampicin) to be adequate in miliary TB, whereas the American Academy of Pediatrics127 advocates 9 months of treatment. In the presence of associated TBM, treatment needs to be given for at least 12 months. The NICE TB guidelines126 suggest that all patients with disseminated (including miliary) TB should be tested for CNS involvement by CT or MRI of the brain and/or lumbar puncture for those without CNS symptoms and signs. They recommend starting ATT even if initial liver functions are abnormal and careful monitoring during follow-up. Appropriate modification of drug treatment should be done if the patient’s liver function deteriorates significantly on ATT. Patients with miliary TB get treated under national TB control programs, with the Directly Observed Treatment, Short-course (DOTS) using short-course, intermittent, thrice-weekly treatment in low-economic-resource countries.123

These observations highlight the importance of accurately assessing the extent of involvement clinically and radiologically. Thus, if underlying TBM remains undiagnosed in a patient with miliary TB, ATT for only 6 months may be suboptimal. Therefore, though the standard duration of treatment may be sufficient for many, each patient needs to be assessed individually, and wherever indicated, treatment duration may have to be extended.

Patients with HIV/tuberculosis coinfection

Sparse data are available regarding the efficacy of standard treatment regimens in the treatment of HIV/miliary TB coinfection. The WHO recommends all patients of suspected or confirmed military TB should be tested for HIV status, and in HIV-infected patients with TB, for antiretroviral treatment to be started after the completion of ATT.128,129 The strategy for initiation of treatment for both TB and HIV infection is shown in Table 4. In cases of HIV/MTB coinfected children, the CDC recommends 12 months’ ATT, including HREZ for 2 months followed by HR for 10 months.125 For children already receiving antiretroviral treatment

(ART) in whom TB is diagnosed, the ART regimen should be reviewed and optimized for treating HIV/TB coinfection and to minimize potential toxicities and drug–drug interactions. Treatment of miliary TB in patients coinfected with HIV requires careful consideration of drug–drug interactions between antituberculosis and antiretroviral drugs.128,130 Coadministration of rifampicin may result in dangerously low levels of antiretroviral agents by inducing the hepatic cytochrome P450 pathway. Rifabutin is preferred over rifampicin, especially when protease inhibitors are used, but it is costly. Efavirenz is preferred over nevirapine, but should be avoided during pregnancy. Recently, there has been a change in the WHO revised recommendations128 based on the Grading of Recommendations Assessment, Development and Evaluation system131 regarding the time of starting antiretroviral drugs, the choice of drugs, and the time of initiation in relation to institution of ATT.

Table 4Strategy for initiation of treatment for both TB and HIV infection

In peripheral hospitals in endemic areas where HIV and TB are common, quality-assured laboratory facilities for HIV enzyme-linked immunosorbent assay, CD4+ T-lymphocyte counts and plasma HIV viral load estimation may not be available. Timing of initiation and ART, choice of ART and ATT regimens, and drug–drug interactions all require careful consideration.

Role of corticosteroids

Published data regarding the role of adjunct corticosteroid treatment in patients with miliary TB are few and with conflicting results.132 A beneficial response was observed in one study,133 although such benefit could not be documented by another study.134 Presence of associated adrenal insufficiency is an absolute indication for corticosteroid administration. Adjunctive corticosteroid treatment may be beneficial in miliary TB with meningeal involvement, large pericardial or pleural effusion, endobronchial TB, IRIS, ARDS, immune complex nephritis, and histiocytic phagocytosis syndrome.3–6,81,82 The benefit of corticosteroid administration in patients with miliary TB merits further evaluation in future studies, especially in the setting of pulmonary function abnormalities.

Prevention

Evidence from published studies indicates that BCG vaccination is effective in reducing the incidence of miliary TB, especially in children.135 However, it is not effective in individuals who are already infected and should not be administered to immunosuppressed hosts. BCG fails to induce immune responses to RD1 antigens, including ESAT6 and CFP10, which are genetically absent from BCG, but also against a new series of M. tuberculosis dormancy (DosR) regulon antigens that are expressed by M. tuberculosis under conditions of intracellular stress (eg, hypoxia), and which may be important in host control of latent infection.136 BCG is also a powerful inducer of Treg, which may dampen immunity to M. tuberculosis as well as booster vaccines. These factors might also explain – at least in part – why BCG revaccination does not afford any added value against TB.137 Targeted tuberculin testing and treatment of latent TB infection is often practiced in countries with low prevalence of TB,125 but drug-induced hepatitis is a potential risk with this intervention. Ongoing research138,139 is likely to provide a more effective vaccine than BCG.

Mortality and prognostic factors

The mortality related to miliary TB is about 15%–20% in children67–71 and 25%–30% in adults.23–38 Mortality is strongly associated with age, mycobacterial burden, the delay in initiation of chemotherapy, and laboratory markers indicative of severity of disease, such as lymphopenia, thrombocytopenia, hypoalbuminemia, and elevated hepatic transaminases.7,34,140

Several factors have been identified as predictors of poor outcome in patients with miliary TB.23–30,32–37,71 Recognition of these factors can alert clinicians managing patients with miliary TB. A 4-point nutritional risk score was defined according to the presence of four nutritional factors: low body mass index (<18.5 kg/m2), hypoalbuminemia (serum albumin < 30 g/L), hypocholesterolemia (serum cholesterol < 2.33 mmol/L), and severe lymphocytopenia (<7 × 105 cells/L). Each risk factor was assigned a value of 1 if present or 0 if absent. Patients with 3 or 4 points were classified to have a high nutritional risk score.141

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Challenges in the treatment of miliary TBTB is unique among the major infectious diseases in that it lacks accurate rapid POC diagnostic tests. Failure to control the spread of TB is largely due to our inability to detect and treat all infectious cases of pulmonary TB in a timely fashion, allowing continued M. tuberculosis transmission within communities. Challenges to effective solutions include lack of access to diagnosis and treatment, the frequent coexistence of epidemics of TB and HIV, and the increasing prevalence of drug-resistant TB.

Miliary TB is a challenge for clinicians. The key practical issues that may pose difficulties while treating a case of miliary TB are listed below.

Choice of the right antituberculosis drug regimen, adding steroids, duration of ATT, inadequacy of laboratory monitoring facilities, and difficulties in managing complications (especially in peripheral centers due to lack of expertise) are all therapeutic challenges. Failure to assess the extent of organ-system involvement initially (eg, TBM) may result in suboptimal duration of therapy.

While treating TB, drugs should be genuine with good bioavailability, which may not be the case in resource-limited nations despite having high disease prevalence.

In HIV-coinfected patients, even with regular antituberculosis drug intake, adequate plasma levels may not be achieved because of malabsorption problems.

Regarding ART and ATT, several issues are still unclear, like sufficient staff training for recognition of adverse effects and close monitoring of codrug toxicities, lack of quality-assured laboratory facilities where the disease is common, and IRIS diagnosis (proper education of patients for recognition of drug toxicities, drug-adherence issues).

Besides these challenges, healing in TB following “successful” treatment results in fibrosis and consequent anatomical and physiological alterations of the involved organs.142–144 The persistence of physiological, immunological, and radiological defects in miliary TB in spite of treatment and the observation of sequelae in treated cases of pulmonary TB patients point out that these patients will not regain optimal health despite achieving a microbiological cure.145

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Conclusion and future directionMiliary TB is a potentially lethal disease that still perplexes even the most experienced clinicians. Newer technological tools should be used to unravel the immunopathologic phenomenon that results in this form of TB. The role of new interferon-γ assays in the diagnosis of miliary TB needs to be explored in the field. An attempt should be made for systematic data collection and reporting to study the global epidemiology of miliary TB through national TB-control programs to ensure that the proposed diagnostic criteria are strictly adhered to. Miliary TB has shown a high mortality despite the availability of effective treatment. The cause of death in patients with miliary TB merits further study. Appropriately designed randomized controlled trials are needed to define the optimum regimen and duration of treatment in miliary TB patients, including those with HIV/AIDS. The role of adjunctive corticosteroid therapy in the treatment of miliary TB to prevent physiological and radiological abnormalities has not been properly studied in controlled clinical trials and needs to be

elucidated in future studies. The scope and utility of PET-CT in assessing the activity of posttreatment residual lesions in miliary TB needs to be ascertained.

Our tools to combat TB are dangerously out of date and ineffective. Besides new tools, we also need new strategies to identify key M. tuberculosis/human host interactions, where we can most likely find M. tuberculosis’s Achilles’ heel. Equally important is that we build high-quality clinical trial capacity and biobanks for TB biomarker identification. The attempt to prepare an ultimate TB vaccine is still a reverie because a mere T-cell-targeting vaccine may not be sufficient; rather, other (innate immune-related) cells, such as natural-killer cells, γδ T cells, DC, or macrophages need to be activated and triggered in a timely fashion.146 Translational research into better TB diagnostics, drugs, and vaccines has increased globally, but an improved understanding of the basic infection biology of this complex disease is required before radically new interventions can be designed. The search for a better vaccine than BCG is still on, and more data on the candidate vaccines that are currently being evaluated are expected to emerge.

The precise immunopathogenesis of pulmonary fibrosis is not adequately understood, and drugs are not presently available to reverse the process. Nevertheless, there are promising results from basic science research that stem cell therapy in the lung may facilitate lung regeneration and repair.147 Research, therefore, should be aimed at unraveling the mystery of the immunopathogenesis of fibrosis and discovering drugs that can avert the incidence of fibrosis and reverse fibrosis once it has developed.

In response to the global emergency of the TB pandemic, the Stop TB Partnership was established by the World Health Assembly in May 2000, which consists of a partners’ forum, a coordinating board, and a partnership secretariat currently hosted by the WHO in Geneva, Switzerland. A promising and important portfolio of new TB diagnostics, new TB drugs and vaccines has been endorsed by the Stop TB Partnership. The challenge now is to complete development and validation of these in high-TB and high-TB/HIV-burden countries and then translate them into clinical practice at peripheral points of health care.148 With limited finances, priority must be given to the development of technologies that will reach those not being served by current diagnostic provision. In the future, therapeutic interventions based on the results of novel diagnostic procedures can be made earlier, leading to improvements in patient care.

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FootnotesDisclosure

The authors report no conflicts of interest in this work.

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